Oxazolidinones represent the first new class of antibacterials to be developed since the quinolones. The oxazolidinones are synthetic antibacterial compounds that are orally or intravenously active against problematic multidrug resistant Gram positive organisms and are not cross-resistant with other antibiotics. See Riedl et al, Recent Developments with Oxazolidinone Antibiotics, Exp. Opin. Ther. Patents (1999) 9(5), Ford et al., Oxazolidinones: New Antibacterial Agents, Trends in Microbiology 196 Vol. 5, No. 5, May 1997 and WO 96/35691.
This invention relates to new oxazolidinones having a cyclopropyl moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species.
The present invention relates to compounds of formula I: 
its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein:
R1 represents
i) hydrogen,
ii) NR5NR6,
iii) CR7R8R9, C(R)2OR14, CH2NHR14, C(xe2x95x90O)R13, C(xe2x95x90NOH)H, C(xe2x95x90NOR13)H, C(xe2x95x90NOR13)R13, C(xe2x95x90NOH)R13, C(xe2x95x90O)N(R13)2, C(xe2x95x90NOH)N(R13)2, NHC(xe2x95x90X1)N(R13)2, (Cxe2x95x90NH)R7, N(R13)C(xe2x95x90X1)N(R13)2, COOR13, SO2R14, N(R13)SO2R14, N(R13)COR14, or (C1-6alkyl)CN, CN, CHxe2x95x90C(R)2, OH, C(xe2x95x90O)CHR13, C(xe2x95x90NR13)R13, NHC(xe2x95x90X1)R13; or
iv) C5-10 heterocycle optionally substituted with 1-3 groups of R7, which may be attached through either a carbon or a heteroatom; 
represents aryl or heteroaryl, heterocycle, heterocyclyl or heterocyclic, provided that in the case of a heteroaryl, heterocycle, heterocyclyl or heterocyclic, the cyclopropyl is not attached to a nitrogen atom on the ring;
R3 represents
i) NR13(C=X2)R12,
ii) NR13(C=X1)R12,
iii) NR13SO2R14,
iv) NR13(CHR13)0-4aryl,
v) NR13(CHR13)0-4heteroaryl,
vi) S(CHR13)0-4aryl,
vii) S(CHR13)0-4heteroaryl,
viii) O(CHR13)0-4aryl, or
ix) O(CHR13)0-4heteroaryl;
x) OCR13=NR16 
R4 and R4a independently represent
i) hydrogen,
ii) halogen,
iii) C1-6 alkoxy,
iv) C1-6 alkyl,
v) CN,
vi) Aryl, or
vii) heteroaryl
r and s independently are 1-3, with the provision that when (R4a)s and (R4)r are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4; 
represents an optionally substituted aromatic heterocyclic group containing at least one nitrogen in the ring and which is attached through a bond on any N, and which is unsubstituted or contains 1 to 3 substituents of R16;
R5 and R6 independently represent
i) hydrogen,
ii) C1-6 alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C1-6 alkoxy, amino, imino, hydroxyamino, alkoxyamino, C1-6 acyloxy, C1-6 alkylsulfenyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, C1-6 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF3, C1-6 alkyl or C1-6 alkoxy;
iii) C1-6 acyl optionally substituted with 1-3 groups of halogen, OH, SH, C1-6 alkoxy, naphthalenoxy, phenoxy, amino, C1-6 acylamino, hydroxylamino, alkoxylamino, C1-6 acyloxy, aralkyloxy, phenyl, pyridine, C1-6 alkylcarbonyl, C1-6 alkylamino, C1-6 dialkylamino, C1-6 hydroxyacyloxy, C1-6 alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
iv) C1-6 alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, amino, hydroxylamino, alkoxylamino, C1-6 acyloxy, or phenyl; said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
v) arylsulfonyl optionally substituted with 1-3 of halogen, C1-6 alkoxy, OH or C1-6 alkyl;
vi) C1-6 alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C1-6 alkoxy, C1-6 acyloxy, or phenyl, said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
vii) aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or phenyl;
viii) five to six membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C1-6 acylamino, C1-6 alkylsulfonylamino, C1-6 alkoxycarbonylamino, C1-6 alkoxy, C1-6 acyloxy or C1-6 alkyl, said alkyl optionally substituted with 1-3 groups of halogen, or C1-6 alkoxy;
ix) C3-6 cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or CN;
x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, C1-6 alkyl, CF3, C1-6 alkanoyl, amino or C1-6 acylamino;
xi) pyrrolylcarbonyl optionally substituted with 1-3 of C1-6 alkyl;
xii) C1-2 acyloxyacetyl where the acyl is optionally substituted with amino, C1-6 alkylamino, C1-6 dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl; or
R5 and R6 taken together with any intervening atoms can form a 3 to 7 membered heterocyclic ring containing carbon atoms and 1-2 heteroatoms independently chosen from O, S, SO, SO2, N, or NR8;
R7 represents
i) hydrogen, halogen, OH, C1-6 alkoxy, C1-6 alkyl, alkenyl,
ii) amino, C1-6 alkylamino, C1-6 dialkylamino, hydroxylamino or C1-2 alkoxyamino all of which can be optionally substituted on the nitrogen with C1-6 acyl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH;
R8 and R8 independently represent
i) H, CN,
ii) C1-6 alkyl optionally substituted with 1-3 halogen, CN, OH, C1-6 alkoxy, C1-6 acyloxy, or amino,
iii) phenyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy; or
R7 and R8 taken together can form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH, and NR8;
X1 represents O, S or NR13, NCN, or NSO2R14;
X2 represents O, S, NH or NSO2R14;
R10 represents hydrogen, C1-6 alkyl or CO2R15;
R11 represents hydrogen, C1-6 alkyl, C1-6 alkanoyl, halogen, amino, C1-6 acylamino, C1-6 alkoxy, OH or CF3,; NHC1-6 alkyl, or N(C1-6 alkyl)2, where said alkyl may be substituted with 1-3 groups of halo, OH or C1-6 alkoxy;
R12 represents hydrogen, C1-6 alkyl, C1-6 cycloalkyl, heteroaryl, wherein said heteroaryl may be substituted with 1-2 groups of C1-6 alkyl, NH2, C1-6 alkylamino, C1-6 alkoxy or C1-6 dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, OH or C1-6 alkoxy; alkylthio, alkylsulfinyl, alkylsulfonyl or cyano;
Each R13 represents independently hydrogen, C1-6 alkyl, NR5R6, SR8, S(O)R8, S(O)2R8, CN, C1-6 alkylS(O)R, OH, C1-6 alkoxycarbonyl, C6-10 arylcarboxy, hydroxycarbonyl, C1-6 acyl,
C3-7 membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO2, NH and NR8 where said C1-6 alkyl or C1-6 acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R)2, CO2R, C6-10 aryl,
C5-10 heteroaryl, or C1-6 alkoxy groups;
When two R13 groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH, and NR8;
R represents hydrogen or C1-6 alkyl;
R14 represents amino, C1-6 alkyl, C1-6 haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C1-6 alkoxy, C1-6 acylamino, or C1-6 alkyl, hydroxy and/or amino, said amino and hydroxy optionally protected with an amino or hydroxy protecting group;
R15 is C1-6 alkyl or benzyl said benzyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, or C1-6 alkyl;
R16 represents CN, NH2, OH, hydroxy C1-6 alkyl, C1-6 alkyl, COOC1-6 alkyl, COOH, CONH2, CON(C1-6 alkyl)2, CONHC1-6 alkyl, CHO, Cxe2x95x90NOH, Cxe2x95x90NOC1-6 alkyl, (CH2)1-3NH2, (CH2)1-6NHOC1-6 alkyl, (CH2)1-6N(C1-6 alkyl)2,
m, n, and q represents 0-1.
Another aspect of the invention is concerned with the use of the novel antibiotic compositions in the treatment of bacterial infections.
The invention is described herein in detail using the terms defined below unless otherwise specified.
The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E. L. Eliel and S. H. Wilen Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994, in particular pages 1119-1190).
When any variable (e.g. aryl, heterocycle, R5, R6 etc.) occurs more than once, its definition on each occurrence is independent at every other occurrence. Also combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight or branched. Preferred alkyl groups include lower alkyls which have from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and t-butyl. When substituted, alkyl groups may be substituted with up to 3 substituent groups, selected from the groups as herein defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with xe2x80x9cbranched alkyl groupxe2x80x9d.
Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When substituted, cycloalkyl groups may be substituted with up to 3 substituents which are defined herein by the definition of alkyl.
Alkanoyl refers to a group derived from an aliphatic carboxylic acid of 2 to 4 carbon atoms. Examples are acetyl, propionyl, butyryl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like. 
refers to aryl or heteroaryl, heterocycle, Het, heterocyclyl or heterocyclic as described immediately below.
Aryl refers to any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, indanonyl, biphenyl, tetralilnyl, tetralonyl, fluorenonyl, phenanthryl, anthryl, acenaphthyl, and the like substituted phenyl and the like. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
The expression 
represents an optionally substituted aromatic heterocyclic group containing 1 to 4 ntrogen atoms and at least one double bond, and which is connected through a bond on any nitrogen. Exemplary groups are 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, tetrazole, pyrazole, and imidazole, any of which may contain 1 to 3 substituents selected from CN, NH2, OH, C1-6 alkyl, COOC1-6 alkyl, COOH, CONH2, CON(C1-6 alkyl)2, CONH(C1-6 alkyl), CHO, Cxe2x95x90NOC1-6 alkyl, (CH2)1-3NH2, NHAc, or N(C1-6 alkyl)2.
The term heterocycle, heteroaryl, Het, heterocyclyl or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 8- to 11-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized (in which case it is properly balanced by a counterion), and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocycle or heterocyclic includes heteroaryl moieties. xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d therefore includes the above mentioned heteroaryls, as well as dihydro and tetrahydro analogs thereof. The heterocycle, heteroaryl, Het or heterocyclic may be substituted with 1-3 groups of R7. Examples of such heterocyclic elements include, but are not limited to the following: piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, naphthpyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrotriazolyl, dihydrothienyl, dihydrooxazolyl, dihydrobenzothiophenyl, dihydrofuranyl, benzothiazolyl, benzothienyl, benzoimidazolyl, benzopyranyl, benzothiofuranyl, carbolinyl, chromanyl, cinnolinyl, benzopyrazolyl, benzodioxolyl and oxadiazolyl. Additional examples of heteroaryls are illustrated by formulas a, b, c and d: 
wherein R16 and R17 are independently selected from hydrogen, halogen, C1-6 alkyl, C2-4 alkanoyl, C1-6 alkoxy; and R18 represents hydrogen, C1-6 alkyl, C2-4 alkanoyl, C1-6 alkoxycarbonyl and carbamoyl.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The terms xe2x80x9cquaternary nitrogenxe2x80x9d and xe2x80x9cpositive chargexe2x80x9d refer to tetravalent, positively charged nitrogen atoms (balanced as needed by a counterion known in the art) including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e.g. tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
The term xe2x80x9cheteroatomxe2x80x9d means O, S or N, selected on an independent basis.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. Exemplary prodrugs include acyl amides of the amino compounds of this invention such as amides of alkanoic(C1-6)acids, amides of aryl acids (e.g., benzoic acid) and alkane(C1-6)dioic acids.
Halogen and xe2x80x9chaloxe2x80x9d refer to bromine, chlorine, fluorine and iodine.
When a group is termed xe2x80x9csubstitutedxe2x80x9d, unless otherwise indicated, this means that the group contains from 1 to 3 substituents thereon.
When a functional group is termed xe2x80x9cprotectedxe2x80x9d, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
Examples of suitable hydroxyl and amino protecting groups are: trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like. Examples of suitable carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, t-butyl and the like.
The cyclopropyl containing oxazolidinone compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects. The term xe2x80x9cpharmaceutically acceptable ester, salt or hydrate,xe2x80x9d refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel cyclopropyl containing oxazolidinone compounds.
The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, when the Formula I compounds are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic or organic acids. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isethionic, lactate, maleate, mandelic, malic, maleic, methanesulfonate, mucic, 2-naphthalenesulfonate, nicotinate, nitric oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, phosphate, pantothenic, pamoic, sulfate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
When the compound of the present invention is acidic, suitable xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable inorganic non-toxic bases include salts of primary, secondary and teritiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
The pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include those which are hydrolyzed under physiological conditions, such as xe2x80x9cbiolabile estersxe2x80x9d, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others.
Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors. Examples of biolabile esters include compounds.
Another embodiment of this invention is realized when R1 independently represent H, NR5NR6, CN, OH, C(R)2OR14, NHC(xe2x95x90X1)N(R13)2, C(xe2x95x90NOH)N(R13)2, or CR7R8R9 and all other variables are as described herein.
Another embodiment of this invention is realized when 
is phenyl, pyridine, pyrimidine, or piperidine and all other variables are as described herein.
Another embodiment of this invention is realized when R1 is NR5R6 and all other variables are as described herein.
Another embodiment of this invention is realized when R1 is CN and all other variables are as described herein.
Still another embodiment of this invention is realized when R5 and R6 independently are:
i) H,
ii) C1-6 alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C1-6 alkoxy, amino, hydroxyamino, alkoxyamino, C1-6 acyloxy, C1-6 alkylsulfenyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, C1-6 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethyenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF3, C1-6 alkyl or C1-6 alkoxy;
iii) C1-6 acyl optionally substituted with 1-3 groups of halogen, OH, SH, C1-6 alkoxy, naphthalenoxy, phenoxy, amino, C1-6 acylamino, hydroxylamino, alkoxylamino, C1-6 acyloxy, phenyl, pyridine, C1-6 alkylcarbonyl, C1-6 alkylamino, C1-6 dialkylamino, C1-6 hydroxyacyloxy, C1-6 alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl; or
iv) benzoyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, C1-6 alkyl, CF3, C1-6 alkanoyl, amino or C1-6 acylamino and all other variables are as described herein.
Yet another embodiment of this invention is realized when X1 represents O and all other variables are as described herein.
A preferred embodiment of this invention is realized when the structural formula is II: 
wherein R1, R4, R4a, and R3 are as described herein.
Another preferred embodiment of this invention is realized when R1 is CN or NR5R6.
Preferred compounds of this invention are:
N-[5(S)-3-[4-[(1-t-Butoxycarbonyl)cyclopropan-1-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Carboxycyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Fluoro-4-(1-hydroxymethylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Aminocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Aminocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Aminocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Fluoro-4-(1-formylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Fluoro-4-(1-(hydroxyimino)methylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]methanesulfonylamide,
N-[5(S)-3-[4-[(1-t-Butoxycarbonyl)cyclopropan-1-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3,5-Difluoro-4-(1-hydroxymethylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3,5-Difluoro-4-(1-formylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazotidin-5-ylmethyl]difluoroacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]aminomethyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2-isoxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]aminomethyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,2,3,4-thiatriazolyl-5-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,2,3,4-thiatriazolyl-5-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2,3,4-thiatriazolyl-5-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2-isoxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)oxy]methyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,3-thiazolyl-2-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,3,4-thiadiazolyl-2-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,3-thiazolyl-2-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,3-thiazolyl-2-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,3-thiazolyl-2-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,3,4-thiadiazolyl-2-yl)amino]methyloxazolidin-2-one,
S-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]dithiocarbamate,
S-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]dithiocarbamate,
S-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]dithiocarbamate,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
O-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbonate,
O-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbonate,
Nxe2x80x2-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
Nxe2x80x2-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
Nxe2x80x2-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thiourea, O-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbonate,
Nxe2x80x2-Cyano N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamidine, and
Nxe2x80x2-Cyano N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidine, or
their enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein.
The compounds of the present invention can be prepared according to the procedures of the following schemes and general examples, using appropriate materials, and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The following examples further illustrate details for the preparation of compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare the compounds of the present invention. All temperatures are in degrees Celsius unless otherwise noted. 
General Schemes for the preparation of the compounds of the present invention are detailed in Schemes I-IV. It should be recognized that the chemical transformations depicted in Schemes I-IV are performed in one possible sequence. It will be recognized by those skilled in the art that modifications of the described schemes can be mentioned in which the requisite transformations can be performed in a different sequence to obtain the compounds of the present invention. Thus, the general sequence of synthetic transformations described below should not be construed as limiting with regard to the preparation of the compounds of the present invention. As shown in Schemes I-II one general procedure for the preparation of the Compounds of the present invention begins from readily available nitroaromatic or nitroheteroaromatic compounds, A, which are optimally substituted with a leaving group (X) appropriate for substitution. In many cases a preferred leaving group is picked from one of the halogens, but those skilled in the art will recognize that in some cases other leaving groups may be substituted such as sulfonyl or phosphoryl ethers. Treatment of the selected compounds with a malonyl ester in the presence of an appropriate base readily selected by practitioners of the art followed by in situ hydrolysis of the resulting diester and decarboxylation under acidic conditions affords the resulting nitro substituted aromatic or heteroaromatic acetic acid. Typical malonyl esters would include ethyl or other lower alkyl esters as well as aryl esters such as phenyl or substituted phenyl esters. Many strong bases can be used for performing this transformation, some preferred bases include metal hydrides such as sodium hydride or potassium hydride along with non-nucleophilic amide bases such as lithium diisopropylamide or the like or alkoxide bases such as sodium ethoxide or sodium methoxide. Likewise a variety of aqueous acids sulfuric acid or hydrochloric acid can be envisioned for the hydrolysis and if necessary appropriate cosolvents such as acetic acid or propionic acid may be employed in the in situ decarboxylation of the intermediate diester to the desired aromatic or heteroaromatic acetic acid. Optionally the hydrolysis mixture may be heated to accelerate the rate of the reaction and often it is convenient to reflux the reaction mixture until the reaction has been completed. In a second step the aromatic or heteroaromatic acetic acid obtained above is esterified to form B. It will be recognized that there are a plethora of potential methods for the preparation of esters from acids and potentially many of them could be used for the preparation of the desired aromatic or heteroaromatic phenylacetic acid ester. While a number of alkyl esters could be formed in the above transformation the use of the t-butyl ester or other tertiary alkyl ester is preferred for the subsequent transformations. These esters may be prepared by a variety of methods such as reacting the aromatic or heteroaromatic phenyl acetic acid in a non-polar solvent with a 1,1-disubstituted olefin in the presence of a strong acid such as sulfuric acid. Alternatively the requisite tertiary alkyl ester B can be formed by in situ formation of an acid chloride or a mixed anhydride and allowing the resulting activated acid to react with a tertiary alcohol such as t-butanol or t-amyl alcohol to form the requisite tertiary ester. Preferred reagents for the activation of the aromatic or heteroaromatic acid include, but are not limited to, oxalyl chloride, thionyl chloride, or di-t-butyldicarbonate.
In the next step the ester B is converted to the acrylate C. A convenient method for the preparation of C is the reaction of B with Bis-N,N-dimethylaminomethane or another appropriate formaldehyde equivalent in an a nonprotic polar solvent such as dimethylsulfoxide or dimethylformamide or the like in the presence of an anhydride such as acetic anhydride. In this way the acrylate C is conveniently prepared and can be converted to the desired 1,1-substituted cyclopropane, D, by reaction with an ylide precursor such as trimethylsulfoxonium iodide in the presence of a non-nucleophilic base such as potassium t-butoxide of sufficient strength to form the requisite ylide.
The nitro cyclopropane D is then reduced to the amino compound and acylated to the carboxybenzyl-protected intermediate E. Numerous methods for the reduction of aromatic and heteroaromatic nitro compound to the corresponding amines will be well known to those familiar with the art and these are incorporated within the scope of the present invention. Particularly useful however is the reduction of the nitro group with hydrogen gas in the presence of a metal catalyst such as platinum, palladium, or ruthenium deposited on an inert carrier such as carbon in an appropriate solvent such as methanol, ethanol, acetic acid, ethyl acetate and the like. Alternatively other reducing agents such as SnCl2 or FeCl3 could be employed in the present reduction. The amine so synthesized is then acylated with an alkylchloroformate such as benzylchloroformate in a non-polar solvent such as tetrahydrofuran, ethyl ether, or methylene chloride to afford the required carboxybenzylprotected amine, E. The oxazolidinones of the present invention are then readily prepared in a stepwise fashion by first deprotonating E in an ethereal solvent such as tetrahydrofuran or diethyl ether with a strong base such as an alkyl lithium, alkyl magnesium halide or a dialkyl lithium amide. Examples of bases appropriate for this transformation would include but are not limited to n-butyl lithium, methyl magnesium bromide, t-butyl lithium, sec-butyl lithium, or lithium diisopropyl amide and the like. Typically the deprotonation is carried out at a reduced temperature in the range of 0xc2x0 C. to xe2x88x92100xc2x0 C. but may be performed at any appropriate temperature. Addition of a glycydyl ester such as glycidyl butyrate followed by warming to room temperature affords the desired 5-hydroxyoxazolidinone, F, of the present invention. It should be noted that if an R-glycydyl ester is used an R-5-hydroxyoxazolidinone will be obtained while if an S-glycydyl ester is employed an S-5-hydroxyoxazloidinone will be obtained. By this way oxazolidinones that are substantially single enantiomers can be prepared. However if racemic F would be desired, it would be readily prepared from an appropriate racemic glycydyl ester.
Optionally, if a 1-cyanosubstituted cyclopropane is desired in the compounds of the present invention the ester D may be converted to the cyano compound G. It will be recognized that there are several methods and reagents for carrying out this transformation. For example the ester may be hydrolyzed to the acid and subsequently reduced to the carbinol. Oxidation to the aldehyde followed by formation of the oxime and dehydration would then afford the cyano compound G. Alternatively the ester may be directly reduced to the carbinol and then converted to G as described above. In another modification of the invention one could directly convert the ester to the aldehyde and thence to G. All of the above methods are incorporated into the present invention. However, a particularly preferred procedure for performing this transformation involves removal of the ester under acidic conditions, such as treatment with trifluoroacetic acid, hydrochloric acid or another appropriate strong acid, conversion of the resulting acid to a mixed anhydride in situ by treatment with a reagent such ethylchloroformate and an amine base such as triethylamine and reduction of the resulting mixed anhydride with a hydride reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, or one of many other appropriate hydride reducing agents well known to practitioners of the art. The resulting carbinol is then oxidized to the aldehyde with reagents suitable for this transformation such as the Dess-Martin reagent or 1-hydroxy-1-benziodoxol-3(1H)-one, dimethylsulfoxide/oxalyl chloride, chromium trioxide pyridine complex, or another reagent chosen from oxidizing agents appropriate for this transformation. The resulting aldehyde is then converted to the oxime using hydroxylamine hydrochloride and an appropriate buffer such as sodium acetate and dehydrated with an appropriate dehydrating agent such as acetic anhydride or diisopropylazodicarboxylate in the presence of triphenyl phosphine to afford the requisite cyano compound, G. In a manner similar to that described above for the transformation of D to F, intermediate G can be converted to the 5-hydroxyoxazolidinone of the present invention H. 
The 5-hydroxyoxazolidinones F and H are useful intermediates for the preparation of compounds of the present invention. In Scheme II further modifications of H are illustrated but it will be realized that similar modifications of F can be performed to form analogous compounds of the present invention and that further modification of both F and H are incorporated within the present invention. The hydroxymethyloxazolidinone H can be converted to a leaving group by treatment with an appropriate reagent. Preferred leaving groups include the mesylate, tosylate, benzenesulfonate, trifluoromethanesulfonate, halides and the like and the methods to produce these intermediates will be readily recognized by those skilled in the art. A preferred leaving group is the mesylate I which may be readily prepared by treatment with methanesulfonylchloride in a nonpolar solvent such as methylene chloride, tetrahydrofuran, diethylether, carbon tetrachloride, dichloroethane and the like using a tertiary amine such as triethylamine as a catalyst. The resulting mesylate I can be further converted to compounds of the present invention by treatment with a variety of nucleophiles which substitute the mesylate radical with the nucleophile radical of the present invention. Examples of nucleophiles that can be used include, but are not limited to sodium azide, sodiumthiocyanate, heterocycles such as 1,2,3-triazole, imidazole, pyrazole and the like optionally activated as their metal salts by the addition of sodium hydride or other such appropriate base. Typical solvents for these reactions include such solvents as dimethylformamide or dimethylsulfoxide which are particularly useful for displacements of this type but may also include less polar solvents such as methylene chloride, tetrahydrofuran, diethyl ether, or alcohol solvents such as methanol, ethanol , or isopropyl alcohol when appropriate. A particularly useful intermediate is the 5-azidomethyl oxazolidinone J. The azide J can be used as a substrate in 1,3-dipolar additions in which a substituent is added to the proximal and distal nitrogens of the azide to afford 1,2,3-triazole analogues. For example treatment of J with norbornadiene at reflux in dioxane affords the 1-substituted, 1,2,3-triazole while treatment with malononitrile affords the 4-cyano-5-amino-1,2,3-triazole. Similarly the 5-hydroxymethyl-1,2,3-triazole can be prepared from J and propargyl alcohol which can itself be transformed to a variety of analogues of the present invention by modifications of the hydroxymethyl group to the aldehyde, oxime, oximemethyl ether, and cyano analogues and the like by methods which will be readily apparent to those of ordinary skill in the art. Treatment of J in a similar manner with t-butyl propiolate affords the t-butyl 1-substituted-1,2,3-triazole-4-carboxylate and the ester can be further transformed to the acid and modified to further amide and ester analogues of the present invention. Alternatively reduction of the ester to the hydroxymethyl analogue would allow further modification as described above for the 5-hydroxymethyl regioisomer.
In addition to being a substrate for 1,3-dipolar additions, the 5-azidomethyl oxazolidinone J can be reduced to the 5-aminomethyl oxazolidinone K. The 5-aminomethyl oxazolidinone can be acylated with a wide variety of acylating agents under appropriate conditions. Examples of acylating agents used to prepare compounds of the present invention include, but are not limited to acetic anhydride, difluoroacetic anhydride, trifluoroacetic anhydride, bis-2(1H)-hydroxypyridine thiocarbonate, methylisothiocyanate, O-methyl-N-cyanoacetamide, propionic anhydride, methylchloroformate, dichloroacetylchloride, N-cyanodithioiminocarbonate, and sulfonyl chlorides such as methane sulfonyl chloride and the like. Alternatively carboxylic acids can be used to acylated the 5-aminomethyloxazolidinone, K. In these modifications the carboxylic acids are typically activated for acylation by conversion to the acid chloride with thionyl chloride or oxalyl chloride or activated in situ with a carbodiimde such as dicyclohexyl carbodiimide. Examples of carboxylic acids that can be used to acylate K include but are not limited to cyclopropanecarboxylic acid, 2-methoxyacetic acid, furn-3-carboxylic acid, pyrazine-2-carboxylic acid, isoxazole-5-carboxylic acid, 1,2,5-thiadiazole-3-carboxylic acid, 4-methylthiazole-5-carboxylic acid, formic acid, methylthioacetic acid, methylsulfonylacetic acid, 2,2,-dichlorocyclopropane-1-carboxylic acid, 2-chloropropionic acid, 1-cyano-cyclopropane-1-carboxylic acid, 1-hydroxycyclopropane-1-carboxylic acid.
One preferred modification of the 5-aminomethyl-oxazolidinone K is the 5-acetamidomethyl oxazolidinone L which is readily prepared from K by treatment with acetic anhydride. The acetamide L can be further modified to the thioacetamide by treatment with Lawesson""s reagent, or alkylated with alkyl halides such as methyl iodide in the presence of a suitable base such as potassium t-butoxide to afford the N-alkylacetamides.
Further compounds of the present invention can be prepared by displacement of the hydroxyl group of the 5-hydroxymethyloxazolidinone H with an appropriate nucleophile. Typically displacements of this sort are carried out under conditions known to those skilled in the art as Mitsunobu conditions. These generally involve in situ activation of H with an azodicarboxylate analogue such as diethylazodicarboxylate, diisopropylazodicarboxylate, or tetramethylazodicarboxamide, in the presence of a phosphine such as tributyl phosphine, triphenyl phosphine or trifuryl phosphine in a suitable solvent such as benzene, ether, toluene, tetrahydrofuran, or methylene chloride. Among the nucleophiles used in such displacement reactions to prepare compounds of the present invention include but are not limited to N-benzoyloxyacetamide heterocycles such as 1,2,4-triazole, pyrazole, 1H-tetrazole, 3-hydroxyisoxazole, and t-butoxycarbonylprotected aminoheterocycles such as 3-N-(t-butoxycarbonyl)amino-1,2,4-oxadiazole, 3-N-(t-butoxycarbonyl)amino-1,2-isoxazole, 2-N-(t-butoxycarbonyl)amino-1,3-thiazole, and 2-N-(t-butoxycarbonyl)amino-1,3,4-thiadiazole, and 2-N-(t-butoxycarbonyl)aminopyridine. In those cases where an amino group is protected as a t-butoxycarbonyl derivative or where an hydroxy is protected by a benzoyl group, these protecting groups can be removed under conditions well known to those skilled in the art to prepare the corresponding amino or hydroxyl analogues of the present invention.
As mentioned above and as shown in Scheme III the 5-hydroxymethyl oxazolidinone F can converted to the mesylate M which can in turn be converted to the 5-azidomethyloxazolidinone N. The 5-azidomethyloxazolidinone N can be reduced to the 5-aminomethyloxazolidinone O which can in turn be acylated to the 5-acetamidooxazolidinone P. These conversions can be carried out in a manner exactly analogous to the conversion of H to L as described in Scheme II. Moreover further modifications of F, M, N, O, and P can be carried out. For example analogous modifications to that described for H can be carried out on F to afford further compounds of the present invention. Likewise, M can be modified analogous to I, N modified analogous J, O modified analogous to K, and P modified analogous to L. All of these analogous modifications are incorporated into the compounds of the present invention. In addition the t-butoxycarbonyl group of F, M, N, O, and P can be independently modified to form further compounds of the present invention. These modifications are exemplified in Scheme IV for compound P, but it will be readily recognized by those with ordinary skill in the art that analogous modifications could be made to F, M, N, or O independently and all of the potential modifications are incorporated into the compounds of the present invention. 
As shown in Scheme IV compound P can be treated with a strong acid such as tnrifuoroacetic acid or hydrochloric acid in a nonpolar solvent such as methylene chloride to afford the carboxylic acid Q. It will be recognized by those with ordinary skill in the art that a variety of methods are known for the conversion of Q to the amine R. In a preferred method Q is treated with triphenylphosphoryl azide in a nonpolar solvent such as methylene chloride in the presence of a tertiary amine base to afford R. Alternatively Q can be reduced to the hydroxymethyl compound S by formation of the mixed anhydride with alkylchloroformate such as ethylchloroformate in the presence of a tertiary amine base and the in situ formed anhydride reduced with aqueous sodium borohydride which after workup in the standard way affords S. As described above a variety of methods are available for the oxidation of primary alcohol to the aldehyde, thus in a preferred, but not limiting transformation S is treated with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide to afford the aldehyde T. The compound T can be converted to the oxime U by treatment with hydroxylamine hydrochloride in an alcoholic solvent such as methanol in the presence of a mild base such as sodium acetate. It should be recognized that dehydration of T by methods described above for the dehydration of oximes provides an alternative method for the preparation of L. 
Suitable subjects for the administration of the formulation of the present invention include mammals, primates, man, and other animals. In vitro antibacterial activity is predictive of in vivo activity when the compositions are administered to a mammal infected with a susceptible bacterial organism.
Using standard susceptibility tests, the compositions of the invention are determined to be active against MRSA and enterococcal infections.
The compounds of the invention are formulated in pharmaceutical compositions by combining the compounds with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below.
The compounds may be employed in powder or crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection (intravenously or intramuscularly).
Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder (lyophilized or non-lyophilized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water. In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize carriers such as conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.
The dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.
The novel antibiotic compositions of this invention for human delivery per unit dosage, whether liquid or solid, comprise from about 0.01% to as high as about 99% of the cyclopropyl containing oxazolidinone compounds discussed herein, the preferred range being from about 10-60% and from about 1% to about 99.99% of one or more of other antibiotics such as those discussed herein, preferably from about 40% to about 90%. The composition will generally contain from about 125 mg to about 3.0 g of the cyclopropyl containing oxazolidinone compounds discussed herein; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg and from about 200 mg to about 5 g of the other antibiotics discussed herein; preferably from about 250 mg to about 1000 mg. In parenteral administration, the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.
The invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal the claimed composition in an amount effective to treat said infection.
The preferred methods of administration of the claimed compositions include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection formulated so that a unit dosage comprises a therapeutically effective amount of each active component or some submultiple thereof.
For adults, about 5-50 mg/kg of body weight, preferably about 250 mg to about 1000 mg per person of the cyclopropyl containing oxazolidinone antibacterial compound and about 250 mg, to about 1000 mg per person of the other antibiotic(s) given one to four times daily is preferred. More specifically, for mild infections a dose of about 250 mg two or three times daily of the cyclopropyl containing oxazolidinone antibacterial compound and about 250 mg two or three times daily of the other antibiotic is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg each of the cyclopropyl containing oxazolidinone and the other antibiotics, three or four times daily is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of about 500-2000 mg each of the cyclopropyl-containing oxazolidinone compound and the other antibiotics, three to four times daily may be recommended.
For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg is typically recommended.
The invention is further described in connection with the following non-limiting examples.
The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard bacterial strains, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against vancomycin-resistant enterococci, streptococci including penicillin-resistant S. pneumoniae, methicillin-resistant S. aureus, M. catarrhalis, and C. pneumoniae. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The following in vitro results were obtained based on an agar dilution method except for C. pneumoniae. The activity is presented as the minimum inhibitory concentration (MIC) S. aureus and M. catarrhalis were tested on Mueller-Hinton agar, using an approximate inoculum of 1xc3x97104 cfu/spot an incubation temperature of 35C for 24 hours. The MIC was defined as the lowest concentration at which no visible bacterial growth was observed.
Streptococci and enterococci were tested on Mueller-Hinton agar supplemented with 5% defibrinated horse blood, using an approximate inoculum of 1xc3x97104 cfu/spot an incubation temperature of 35C in an atmosphere of 5% CO2 for 24 hours. The MIC was defined as the lowest concentration at which no visible bacterial growth was observed.
C. pneumoniae was tested using minimum essential medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 1 mg/ml cycloheximide and non essential amino acid. HeLa 229 cells were inoculated with 104 inclusion-forming units of C. pneumoniae strain per mL. Infected cells were incubated with test compounds in complete medium at 35C in an atmosphere of 5% CO2 for 72 hours. Cells monolayers were fixed in methanol, stained for chlamydial inclusions with an fluorescein-conjugated anti-Chiamydia monoclonal antibody, and were observed with fluorescence microscope. The MIC was defined as the lowest concentration at which no inclusion was observed.
The invention described herein is exemplified by the following non-limiting examples. The compound data is designated in accordance to General Guidelines for Manuscript Preparation, J. Org. Chem. Vol. 66, pg. 19A, Issue January, 2001.
The invention described herein is exemplified by the following non-limiting examples. The compound data is designated in accordance to General Guidelines for Manuscript Preparation, J. Org. Chem. Vol. 66, pg. 19A, Issue January, 2001.